In vitro and in vivo inhibitory effect of stiripentol on clobazam metabolism
In vitro and in vivo inhibitory effect of stiripentol on clobazam metabolism
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DOI：
10.1124/dmd.105.007237
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发表时间：
2006-04-01
影响因子：
3.9
通讯作者：
Tran, A
中科院分区：
文献类型：
--
作者：
Giraud, C;Treluyer, JM;Tran, A
在体内观察到司替戊醇 (STP)（一种抑制多种细胞色素 P450 (P450s) 活性的抗惊厥药）和氯巴扎姆 (CLB)（一种 1,5-苯二氮卓类药物，与 STP 联合用于治疗婴儿严重肌阵挛性癫痫）之间的代谢相互作用。使用 cDNA 表达的 CYP3A4 和 CYP2C19（参与 CLB 代谢的主要 P450）在体外表征这种相互作用，以计算司替戊醇与酮康唑（CYP3A4 抑制剂）和奥美拉唑（CYP2C19 抑制剂）相比的 K-i 和 IC50。 STP 抑制 CYP3A4（非竞争性）和 CYP2C19（竞争性）介导的 CLB N-去甲基化为 N-去甲基氯巴占 (NCLB)，K-i = 1.59 +/- 0.07 和 0.516 +/- 0.065 mu M，IC50 = 1.58 mu M [95% 置信区间 (CI95%) =分别为1.20-2.08]和3.29μM（CI95%=1.87-5.79）。 STP 还更强烈地抑制 CYP2C19 将 NCLB 4'-羟基化为 4'-羟基-N-去甲基氯巴占 [与 K-i = 0.139 +/- 0.025 mu M 的竞争性相互作用，IC50 = 0.276 mu M (CI95% = 0.206-0.371)]。 STP对CYP3A4引起的CLB去甲基化的抑制作用远弱于酮康唑[IC50 = 0.023 μM (CI95% = 0.016-0.033)]，而其对CYP2C19引起的NCLB羟基化的抑制作用则远高于奥美拉唑[IC50 = 2.99 μM (CI95% = 0.016-0.033)]。 2.11-4.24）]。 STP 对 CLB 代谢和主要对 NCLB 生物转化的主要体外抑制作用与 CLB/STP 联合治疗儿童体内 CLB 和 NCLB 血浆浓度的变化一致。
A metabolic interaction between stiripentol (STP), an anticonvulsant agent that inhibits the activity of several cytochromes P450 (P450s), and clobazam (CLB), a 1,5-benzodiazepine, used in association with STP in severe myoclonic epilepsy in infancy was observed in vivo. This interaction was characterized in vitro using cDNA-expressed CYP3A4 and CYP2C19 (main P450 involved in CLB metabolism) to calculate K-i and IC50 of stiripentol in comparison with ketoconazole (CYP3A4 inhibitor) and omeprazole (CYP2C19 inhibitor). STP inhibited N-demethylation of CLB to N-desmethylclobazam (NCLB) mediated by CYP3A4 (noncompetitively) and CYP2C19 (competitively) with K-i = 1.59 +/- 0.07 and 0.516 +/- 0.065 mu M and IC50 = 1.58 mu M [95% confidence interval (CI95%) = 1.20-2.08] and 3.29 mu M (CI95% = 1.87-5.79), respectively. STP inhibited also more strongly the 4'-hydroxylation of NCLB to 4'-hydroxy-N-desmethylclobazam by CYP2C19 [competitive interaction with K-i = 0.139 +/- 0.025 mu M and IC50 = 0.276 mu M (CI95% = 0.206-0.371)]. The inhibitory effect of STP on CLB demethylation by CYP3A4 was much weaker than that of ketoconazole [IC50 = 0.023 mu M (CI95% = 0.016-0.033)], whereas its effect on NCLB hydroxylation by CYP2C19 was much higher than that of omeprazole [IC50 = 2.99 mu M (CI95% = 2.11-4.24)]. The major in vitro inhibitory effect of STP on CLB metabolism and mostly on NCLB biotransformation is consistent with the changes in vivo in CLB and NCLB plasma concentrations in children treated by the association CLB/STP.